The long term objective of this application is to demonstrate that adult ventricular myocytes are composed of a large population of terminally differentiated cells and a small group of myocytes which can reenter the cell cycle and divide repeatedly throughout life. The distinction dictates that replicative senescence may be the mechanism of cellular aging in dividing cells, while different processes may be implicated in senescence of non-replicating myocytes. Since proliferating cells have a finite number of population doublings, aging may result in telomeric shortening and attenuation of telomerase activity in multiplying myocytes, leading to growth arrest and senescence. Differentiated cells, however, may hypertrophy progressively with age, achieving a maximum size beyond which no further enlargement occurs. Senescence is then reached In both cases, inhibition of growth and age-dependent changes may increase the susceptibility of senescent myocytes to die in response to apoptotic and/or necrotic death signals. Conditions of overload produced by large myocardial infarcts may change the dynamics of cellular aging by exhausting the hyperplastic and hypertrophic growth reserve of myocytes and, thereby, provoking cellular senescence. The possibility is raised that in the normal and pathologic mammalian heart, myocyte growth, senescence and death are modulated by the cellular insulin-like growth factor-1 (IGF-1) system and the local renin-angiotensin system (RAS). IGF-1 stimulates myocyte division and cell survival, delaying the occurrence of cellular senescence and death. Conversely, Ang II induces myocyte hypertrophy, promoting cellular senescence and death. Importantly, IGF-1 downregulates the myocyte RAS, opposing the deleterious effects of Ang II on cardiac aging. This may be mediated by the ability of IGF-1 to decrease p53 function and the consequent upregulation of the myocyte RAS. Studies will be performed in normal mice and in transgenic mice overexpressing IGF-1 to establish whether this growth factor enhances cell division, attenuates telomere shortening and increases telomerase activity, interfering with cellular senescence in the aging and stressed heart.